Lipid oxidation products in ischemic porcine heart tissue

Dudda, Angela; Spiteller, Gerhard; Kobelt, Frank

doi:10.1016/0009-3084(96)02557-1

Cited by 76 publications

(46 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, monoepoxides of linoleic acid are known to cause disruption of mitochondrial function before cell death at pathologically relevant concentrations (1); they also induce chemotaxis in human neutrophils (18) and are associated with several inflammatory diseases. Leukotoxins as well as other epoxides of unsaturated fatty acids have been identified in infracted tissue, in which their amounts increased over time during ischemia compared with the surrounding healthy heart tissue (19).…”

mentioning

confidence: 99%

Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides

Quéré

Plée-Gautier

Potin

et al. 2004

Journal of Lipid Research

View full text Add to dashboard Cite

CYP4F isoforms are involved in the oxidation of important cellular mediators such as leukotriene B 4 (LTB4) and prostaglandins. The proinflammatory agent LTB4 and cytotoxic leukotoxins have been associated with several inflammatory diseases. We present evidence that the hydroxylation of Z 9(10)-epoxyoctadecanoic, Z 9(10)-epoxyoctadec-Z 12-enoic, and Z 12(13)-epoxyoctadec-Z 9-enoic acids and that of monoepoxides from arachidonic acid [epoxyeicosatrienoic acid (EET)] is important in the regulation of leukotoxin and EET activity. These three epoxidized derivatives from the C18 family (C18-epoxides) were converted to 18-hydroxy-C18-epoxides by human hepatic microsomes with apparent K m values of between 27.6 and 175 M. Among recombinant P450 enzymes, CYP4F2 and CYP4F3B catalyzed mainly the -hydroxylation of C18-epoxides with an apparent V max of between 0.84 and 15.0 min ؊ 1 , whereas the apparent V max displayed by CYP4F3A, the isoform found in leukocytes, ranged from 3.0 to 21.2 min ؊ 1 . The rate of -hydroxylation by CYP4A11 was experimentally found to be between 0.3 and 2.7 min ؊ 1 . CYP4F2 and CYP4F3 exhibited preferences for -hydroxylation of Z 8(9)-EET, whereas human liver microsomes preferred Z 11(12)-EET and, to a lesser extent, Z 8(9)-EET. Moreover, vicinal diol from both C18-epoxides and EETs were -hydroxylated by liver microsomes and by CYP4F2 and CYP4F3. These data support the hypothesis that the human CYP4F subfamily is involved in the -hydroxylation of fatty acid epoxides. These findings demonstrate that another pathway besides conversion to vicinal diol or chain shortening by ␤ -oxidation exists for fatty acid epoxide inactivation. -Le Quéré, V., E. Plée-Gautier, P. Potin, S. Madec, and J-P. Salaün. Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides.

show abstract

mentioning

confidence: 99%

Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides

Quéré

Plée-Gautier

Potin

et al. 2004

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Diols derived from epoxy-linoleate (leukotoxin) perturb membrane permeability and calcium homeostasis (5), resulting in inflammation modulated by nitric oxide synthase and endothelin-1 (7,8). Micromolar concentrations of leukotoxin reported in association with inflammation and hypoxia (9) depress mitochondrial respiration in vitro (10) and cause mammalian cardiopulmonary toxicity in vivo (7,11,12). Leukotoxin toxicity presents symptoms suggestive of multiple organ failure and acute respiratory distress syndrome (9).…”

mentioning

confidence: 99%

Potent urea and carbamate inhibitors of soluble epoxide hydrolases

Morisseau

Goodrow

Dowdy

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

233

278

View full text Add to dashboard Cite

The soluble epoxide hydrolase (sEH) plays a significant role in the biosynthesis of inf lammation mediators as well as xenobiotic transformations. Herein, we report the discovery of substituted ureas and carbamates as potent inhibitors of sEH. Some of these selective, competitive tightbinding inhibitors with nanomolar K i values interacted stoichiometrically with the homogenous recombinant murine and human sEHs. These inhibitors enhance cytotoxicity of transstilbene oxide, which is active as the epoxide, but reduce cytotoxicity of leukotoxin, which is activated by epoxide hydrolase to its toxic diol. They also reduce toxicity of leukotoxin in vivo in mice and prevent symptoms suggestive of acute respiratory distress syndrome. These potent inhibitors may be valuable tools for testing hypotheses of involvement of diol and epoxide lipids in chemical mediation in vitro or in vivo systems.Epoxide hydrolases (EH; E.C.3.3.2.3) catalyze the hydrolysis of epoxides or arene oxides to their corresponding diols by the addition of water (1). In mammals, the hepatic microsomal and soluble epoxide hydrolase forms are known to complement each other in detoxifying a wide array of mutagenic, toxic, and carcinogenic, xenobiotic epoxides (2, 3). Soluble EH (sEH) is also involved in the metabolism of arachidonic (4) and linoleic (5) acid epoxides. Arachidonate epoxides and diols are elevated in association with pregnancy-induced hypertension and modulate vascular permeability in the heart and kidneys (6). Diols derived from epoxy-linoleate (leukotoxin) perturb membrane permeability and calcium homeostasis (5), resulting in inflammation modulated by nitric oxide synthase and endothelin-1 (7, 8). Micromolar concentrations of leukotoxin reported in association with inflammation and hypoxia (9) depress mitochondrial respiration in vitro (10) and cause mammalian cardiopulmonary toxicity in vivo (7,11,12). Leukotoxin toxicity presents symptoms suggestive of multiple organ failure and acute respiratory distress syndrome (9). In both cellular and organismal models, leukotoxin-mediated toxicity depends on epoxide hydrolysis (5).The bioactivity of these epoxide hydrolysis products and their association with inflammation suggest that inhibition of vicinal-dihydroxylipid biosynthesis may have therapeutic value, making sEH a promising pharmacological target. Previously described selective sEH inhibitors, substituted chalcone oxides (as compound 1 in Table 1), and phenylglycidols (13,14) are epoxides that are hydrolyzed slowly by the target enzyme. Inhibition stems from an electronically stabilized covalent intermediate that results in low turnover and transient inhibition (15). Moreover, these compounds are relatively unstable, particularly in the presence of glutathione (13), making them of limited use in vivo. We describe herein the discovery of new potent and stable inhibitors of soluble EH and their application to both in vitro and in vivo models. MATERIALS AND METHODSSynthesis. Compounds 2, 3, 7-9, and 11-18 were obtained from Aldri...

show abstract

mentioning

confidence: 99%

“…EOA has also been shown to cause cardiac arrest in dogs (Fukushima et al, 1988) and relax pulmonary artery smooth muscle (Takahashi et al, 1992). In pig experimentally induced cardiac ischemia caused EOA to increase from undetectable levels to on the order of 1 g/g tissue (Dudda et al, 1996).Recent studies have questioned whether EOA is the toxic agent involved, because it may be further metabolized by epoxide hydrolases to form 9,10-dihydroxy-12-octadecenoic acid (DHOA) (Moghaddam et al, 1997). Both EOA and DHOA have been reported to be toxic in humans and various animal preparations (Fukushima et al, 1988;Kosaka et al, 1994).…”

mentioning

confidence: 99%

“…Both EOA and DHOA have been reported to be toxic in humans and various animal preparations (Fukushima et al, 1988;Kosaka et al, 1994). During myocardial ischemia in pig hydroxy-metabolites of linoleic acid were found to increase from 1 to 3 g/g tissue up to 4 to 22 g/g tissue, depending on the metabolite formed (Dudda et al, 1996). Studies have suggested that EOA must be metabolized to DHOA before producing toxic effects (Moghaddam et al, 1997;Greene et al, 2000).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Differential Effects of Linoleic Acid Metabolites on Cardiac Sodium Current

Harrell

Stimers²

2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

9,10-Epoxy-12-octadecenoic acid (EOA), a metabolite of linoleic acid, causes cardiac arrest in dogs. Other metabolites of linoleic acid also have toxic effects. This study investigates the mechanism of action of four of these compounds on cardiac Na ϩ current (I Na ). The whole-cell patch-clamp technique was used to investigate the effects of EOA, 9,10-dihydroxy-12-octadecenoic acid (DHOA), and their corresponding methyl esters (9,10-epoxy-12-octadecenoic methyl ester, EOM; and 9,10-dihydroxy-12-octadecenoic methyl ester, DHOM) on I Na in isolated adult rat ventricular myocytes. Extracellular application of each compound elicited a concentration-dependent inhibition of I Na . The dose-response curve yielded 50% inhibition concentrations of 301 Ϯ 117 M for DHOA, 41 Ϯ 6 M for DHOM, 34 Ϯ 5 M for EOA, and 160 Ϯ 41 M for EOM. Although there was no effect on activation, 50 M DHOM, EOA, and EOM significantly hyperpolarized the steady-state inactivation curve by approximately Ϫ6 mV. Furthermore, EOM significantly increased the slope of the steady-state inactivation curve. These compounds also seemed to stabilize the inactivated state because the time for recovery from inactivation was significantly slowed from a control value of 12.9 Ϯ 0.5 ms to 30.5 Ϯ 3.3, 31.4 Ϯ 1.4, and 20.5 Ϯ 1.0 ms by 50 M DHOM, EOA, and EOM, respectively. These compounds have multiple actions on Na ϩ channels and that despite their structural similarities their actions differ from each other. The steady-state block of I Na suggests that either the pore is being blocked or the channels are prevented from gating to the open state. In addition, these compounds stabilize the inactivated state and promote increased population of a slower inactivated state.The role of fatty acids in signaling processes is becoming increasingly important. Various fatty acids have been shown to alter several ion currents, including Na ϩ (Xiao et al., 1995;Kang and Leaf, 1996), Ca 2ϩ (Huang et al., 1992;Hashimoto et al., 1999) Bogdanov et al., 1998;Crumb et al., 1999), and Cl Ϫ (Ordway et al., 1991). Arachidonic acid (C20:4) has been widely studied for the actions of the parent compound as well as the extensive metabolic pathways, including the prostaglandins and leukotrienes. Although less widely studied, linoleic acid (C18:2) is a major component of cell membrane phospholipids and is subject to some of the same metabolic pathways. A linoleic acid metabolite (LAM) of interest is 9,10-epoxy-12-octadecenoic acid (EOA), also known as leukotoxin. EOA is formed by lipid autoxidation in the lungs (Sevanian et al., 1979) and by spontaneous reaction of oxygen radicals with linoleic acid in neutrophil membranes (Hayakawa et al., 1996) (Fig. 1). Although undetectable in normal patients (Hayakawa et al., 1990), EOA has been associated with acute respiratory distress syndrome in burn patients where it can reach plasma concentrations up to 300 M (mean peak plasma concentration of 99 Ϯ 25 M) (Kosaka et al., 1994). EOA has also been shown to cause cardiac arrest in dogs (Fukush...

show abstract

Lipid oxidation products in ischemic porcine heart tissue

Cited by 76 publications

References 31 publications

Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides

Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides

Potent urea and carbamate inhibitors of soluble epoxide hydrolases

Differential Effects of Linoleic Acid Metabolites on Cardiac Sodium Current

Contact Info

Product

Resources

About